(−)-R-Homocitric acid lactone is an intermediate of biosynthesis of lysine in yeast and some fungi (Strassman, M.; Ceci, L. N. Biochem. Biophys. Res. Commun., 1964, 14, 262. Strassman, M.; Ceci, L. N. J. Biol. Chem, 1965, 240, 4357. Hogg, R. W.; Broquist, H. P. J. Biol. Chem, 1968, 243, 1839). That pathway is absent in plants and mammalians. Homocitric acid is also an important component of the FeMo-cofactor in nitrogenase, which is fixing air nitrogen (Georgiadis, M. M.; Komiya, H.; Chakrabarti, P.; Woo, D.; Kornuc, J. J.; Rees, D. Science 1992, 257, 1653. Kim, J.; Rees, D. C. Science 1992, 257, 1677. Einsle, O.; Tezcan, F. A.; Andrade, S. L. A.; Schmid, B.; Yoshida, M.; Howard, J. B; Rees, D. C. Science 2002, 297, 1696.).
Racemic homocitric acid has been synthesized starting from diethyl-α-ketoadipate cyanohydrin (Maragoudakis, M., Strassman, M. J. Biol. Chem., 1966, 241, 695) and also from ethyl tert-butyl malonate in a three step procedure in 54% yield (Li, Z.-C.; Xu, J.-Q. Molecules, 1998, 3, 31).
The enantiomers of homocitric acid have obtained by resolution of racemates that were obtained from the chemical synthesis in 10% overall yield (Ancliff, R. A., Rusell, T. A., J. Sanderson, A. J. Tetrahedron: Asymmetry, 1997, 8, 3379).
S-homocitric acid have been obtained as an analytical sample by chemical synthesis starting from optically active (−)-quinic acid (Thomas, U., Kalaynpur, M. G., Stevens, C. M. Biochemistry, 1966, 5, 2513). Also, S- and R-enantiomers of homocitric acid γ-lactones have been chemically synthesized starting from natural enantiomeric L-lactic acid and L-serine in a multistep procedure in low overall yield (Rodriguez, G. H., Bielmann J.-F. J. Org. Chem. 1996, 61, 1822).
The R-enantiomer of homocitric acid sodium salt was preparatively synthesized from D-malic acid Na-salt in 12% yield using a multiple step procedure (Ma, G.; Palmer, D. R. J. Tetrahedron Lett. 2000, 41, 9209). An improved synthesis of R-homocitric acid and 5-homocitric acid from natural D- and L-malic acid correspondingly in a three step procedure in 32-33% overall yield was accomplished (Xu, P.-F.; Matsumoto, Y.; Ohki, Y.; Tatsumi, K. Tetrahedron Letters, 2005, 46, 3815 Xu, P.-F.; Tatsumi, K. Japan Patent Application, 2005, JP2005-075734). Also, a method for preparation of R-homocitric acid trisodium salt from citric acid has been reported (Prokop, M., Milewska, M. J. Polish Journal of Chemistry, 2009, 83, 1317-1322).
A process for preparation of racemic homocitic acid lactone is known (Cai, Qirui Chen, Cai Qirui, Chen Hongbin, Huang Peiqiang, Zhou Zhaohui. Preparation of racemic homocitric acid lactone CN 1948299 (A) 2007-04-18). According to this method (±)-homocitric acid lactone is prepared starting from 2-oxoglutaric acid. Also, a similar patent for the synthesis of racemic homocitic acid lactone starting similarly from 2-ketoglutaric acid is known (Peiquiang, Chen Huang, Huang Peiqiang, Chen Lingyan, Zhang Honkui, CN1927853 (A) 2007-03-14). A method for synthesis of optically active homocitric acid starting from malic acid is known (Tatsumi Kazuyuki, Suu Penfei, Method for producing optically active homocitric acid. JP 2005075734 (A)).
An asymmetric synthesis procedure for optically active R- and S-homocitric acid starting from an achiral 3-hydroxyethyl cyclopentane-1,2-dione is described in Paju, A.; Kanger, T.; Pehk, T.; Eek, M.; Lopp, M. Tetrahedron, 2004, 60, 9081. Lopp, M.; Paju, A.; Pehk, T.; Eek, M.; Kanger, T. Estonian Patent EE 04848 B1. Another asymmetric synthesis procedure for R-homocitric acid and S-homocitric acid lactones and salts, starting from achiral (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters is also known (Lopp, M.; Paju, A.; Eek, M.; Laos, M; Pehk, T. Estonian Patent EE05449B1; U.S. Pat. No. 8,148,568 B2). According to this procedure the starting compounds are (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters, which are transformed to the target compounds homocitric acid lactone and homocitric acid salts by using asymmetric oxidation procedure. The preparation of the starting compounds (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters is not described.
The only publication describing the preparation procedure of (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters, particularly the corresponding tAm ester is described by Reile et al. (Reile I., Paju, A.; Eek, M.; Pehk, T.; Lopp, M. Aerobic Oxidation of Cyclopentane-1,2-diols to Cyclopentane-1,2-diones on Pt/C Catalyst. Synlett, 2008 (3), 347-350). According to that procedure 2-cyclopentene-1-acetic acid is transformed to 2-cyclopentene-1-acetic acid tAm ester by transesterification according to a known procedure (Frei, U., Kirchmayr, R. EP 0278914). The resulted 2-cyclopentene-1-acetic acid tAm ester is dihydroxylated by using fiber bound OsO4 (0.1 mol %) and NMO (1.3 equiv) in H2O-tBuOH 1:3 mixture at 60° C., resulting in (2,3-dihydroxycyclopentenyl)-acetic acid tAm ester. This compound is oxidized with air oxygen in the presence of 5 mol % Pt/C catalyst in MeCN—H2O 1:1 mixture, in the presence of 1 equivalent of LiOH. The target compound (2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid tAm ester was obtained in 28% yield after separation and purification.
There is a need to novel and economic methods to produce 2-hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid esters, which are the starting compounds in the industrial production of homocitric acid. Homocitric acid is a nitrogenase co-factor, which is used in production of nitrogen fertilizers from air nitrogen.